Dual Role of ROS as Signal and Stress Agents: Iron Tips the Balance in favor of Toxic Effects

Elena Gammella, Stefania Recalcati, and Gaetano Cairo. Oxidative Medicine and Cellular Longevity, Volume 2016 (2016), Article ID 8629024, 9 pages, doi:10.1155/2016/8629024

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Abundant evidence shows that a number of neurodegenerative disorders are characterized by regional iron accumulation in particular areas of the central and/or peripheral nervous systems.
This is often caused by cellular iron redistribution and may result in iron-catalyzed Fenton chemistry.Friedrich's ataxia (FRDA) is a paradigmatic example because the disruption of iron homeostasis in this disease has been well defined. The disease results from loss of function mutations (most often triplet expansion) in the FXN gene that lead to decreased expression of frataxin, a mitochondrial iron-binding protein that interacts with proteins involved in the mitochondrial Fe-S cluster biogenesis. In patients, frataxin deficiency results in disruption of Fe-S cluster biosynthesis, severe mitochondrial iron overload, a hallmark of Fe-S defects, and increased sensitivity to oxidative stress.

Time-resolved functional analysis of acute impairment of frataxin expression in an inducible cell model of Friedreich ataxia

Dörte Poburski, Josefine Barbara Boerner, Michel Koenig, Michael Ristow, René Thierbach. Biology Open 2016 : doi: 10.1242/bio.017004

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Here, we have developed a new mammalian cell model employing the Cre/loxP recombination system to induce a homozygous or heterozygous frataxin knockout in mouse embryonic fibroblasts. Induction of Cre-mediated disruption by tamoxifen was successfully tested on RNA and protein levels. The robustness of the newly established system may additionally be used for a time-resolved study of pharmacological candidates in a HTS manner.

Nrf2 activation in the treatment of neurodegenerative diseases: a focus on its role in mitochondrial bioenergetics and function

Noemí Esteras, Albena T. Dinkova-Kostova, Andrey Y. Abramov. Biological Chemistry. Volume 397, Issue 5, Pages 383–400, ISSN (Online) 1437-4315, ISSN (Print) 1431-6730, DOI: 10.1515/hsz-2015-0295, January 2016

As part of its cytoprotective activity, increasing evidence supports its role in metabolism and mitochondrial bioenergetics and function. Neurodegenerative diseases are excellent candidates for Nrf2-targeted treatments. Most neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, frontotemporal dementia and Friedreich’s ataxia are characterized by oxidative stress, misfolded protein aggregates, and chronic inflammation, the common targets of Nrf2 therapeutic strategies.

Cardiac Serum Biomarkers in Friedreich Ataxia May Reflect Fibrosis, Myocyte Injury, and Degree of Hypertrophy

C. Bui, R.B. Wilson, D.R. Lynch, J.W. Rossano, O. Elci, K.Y. Lin, The Journal of Heart and Lung Transplantation, Volume 35, Issue 4, Supplement, April 2016, Page S172, ISSN 1053-2498, doi:10.1016/j.healun.2016.01.479.

We hypothesized that serum markers of cardiac injury, stress, fibrosis, and inflammation are higher in FA subjects than non-FA controls, and these markers correlate with echocardiographic markers of cardiomyopathy.

Abundance and Significance of Iron, Zinc, Copper, and Calcium in the Hearts of Patients with Friedreich Ataxia

Pamela C. Kruger, Karl X. Yang, Patrick J. Parsons, Alyssa B. Becker, Paul J. Feustel, Arnulf H. Koeppen. The American Journal of Cardiology, Available online 20 April 2016, ISSN 0002-9149, doi: 10.1016/j.amjcard.2016.04.024.

Total levels of Fe in bulk extracts were not significantly higher than normal, and the concentrations of Zn also remained in the normal range. Cu levels, however, were significantly lower in FA.

Idebenone in Friedreich ataxia and Leber’s hereditary optic neuropathy: close mechanisms, similar therapy?

Manuel Schiff, Pierre Rustin. Brain (2016) aww085 DOI: 10.1093/brain/aww085 First published online: 19 April 2016

"Yet despite these studies, there is no clear consensus on the benefits of idebenone therapy for patients with Friedreich ataxia. Nevertheless, being essentially harmless idebenone has been, and is still, given to many patients with Friedreich ataxia all over the world."

However, for legal and/or marketing reasons, recent idebenone authorization for LHON resulted in some patients with Friedreich ataxia having difficulty obtaining it.

So far the occurrence of potential responders to idebenone in Friedreich ataxia has not been rigorously examined, but in view of the data obtained in LHON, defining a subgroup of therapy-responder patients appears a reasonable objective for next trials in this (and other) rare disease.

Plasma circulating cell-free mitochondrial DNA in the assessment of Friedreich's ataxia

Subrahamanyam Dantham, Achal K. Srivastava, Sheffali Gulati, Moganty R. Rajeswari, Journal of the Neurological Sciences, Available online 14 April 2016, ISSN 0022-510X, doi:10.1016/j.jns.2016.04.016.

Despite several therapies under study or in development for FRDA, evaluation of therapeutic efficacy is limited by the lack of minimally invasive biomarkers to assess disease progression and severity.
Our study identified three major findings, 1. FRDA patients showed decrease in the levels of plasma mtDNA, whereas plasma nDNA was increased. 2. Plasma mtDNA has shown to exhibit high sensitivity and specificity in discriminating FRDA patients from the healthy controls over plasma nDNA levels 3. Significant serial changes have been observed in case of plasma mtDNA upon intervention with nutrient supplement (omega-3 fatty acids).
In view of their neuro-cardio protective role and positive effect on mitochondrial metabolism in ameliorating the neuro symptoms, the Omega-3 fatty acids (Eicosapentaenoic acid and docosahexaenoic acid) have been recommended as a nutritional supplement

Two different pathogenic mechanisms, dying-back axonal neuropathy and pancreatic senescence, are present in the YG8R mouse model of Friedreich ataxia

Belén Mollá, Fátima Riveiro, Arantxa Bolinches-Amorós, Diana C. Muñoz-Lasso, Francesc Palau, Pilar González-Cabo. Disease Models and Mechanisms 2016 : doi: 10.1242/dmm.024273

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These results confirm that the lack of frataxin induces different pathogenic mechanisms in nervous system and pancreas in the mouse model of FRDA: sensory nerve dying-back and pancreatic senescence.

Original Research Proposal: Creation of an Iron Sensing FXN mRNA Therapeutic Riboswitch for the Treatment of Friedreich's Ataxia

Stephanie Mack, Das Research Group, Department of Chemistry, Carnegie Mellon University

 Location: Mellon Institute Room 355

Development of an AAV9 coding for a 3XFLAG-TALEfrat#8-VP64 able to increase in vivo the human frataxin in YG8R mice

P Chapdelaine, C Gérard, N Sanchez, K Cherif, J Rousseau, D L Ouellet, D Jauvin and J P Tremblay. Gene Ther. accepted article preview 2016 Apr 15. doi: 10.1038/gt.2016.36.

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The study indicates that an AAV coding for a TALE protein coupled with a TAD may be used to increase gene expression in vivo as a possible treatment not only for FRDA but also for other haploinsufficiency diseases.